Blood coagulation is a complex and dynamic biological process that depends on a series of interdependent biochemical reactions. In each step of the series, an active protease is generated from an inactive precursor. Each newly generated protease, in turn, acts on its substrate, another precursor protease, to generate a cascading reaction. This cascade produces ultimately sufficient active thrombin to generate a stable clot.
The terminal portion of this cascade occurs on phospholipid membrane of a platelet. On this surface, Factor IXa (activated by Factor XIa or VIIa, illustrated in FIG. 1), and in the presence of its co-Factor, Factor VIII, activates Factor X to Factor Xa. Factor Xa activates prothrombin to thrombin, which then activates fibrinogen to form the fibrin clot. Factor VII's specific role is to enhance Factor IXa's catalysis of Factor X, as Factor IXa alone can only slowly activate Factor X in vitro. (van Dieijen et al, J Biol Chem. 1981 Apr. 10; 256(7):3433-42).
The most common blood coagulation pathology, Hemophilia A, is the X linked hereditary deficiency that leads to reduced levels of circulating Factor VIII in the blood of afflicted individuals. Concentrated Factor VII preparations are used to treat such individuals to restore their circulating FVIII levels to functional levels. However, in approximately 20% of these patients, inhibitory allo-antibodies are produced against FVIII, abrogating the effectiveness of this treatment.
Treatment of patients that have become refractory to replacement FVIII therapy include immune tolerance induction (ITI), replacement therapy with Porcine FVIII, and a variety of preparations that are said to bypass the requirement for FVIII treatment in clotting. These bypassing preparations include recombinant FVIIa, Prothrombin Complexes Concentrates and activated Prothrombin Complex Concentrates (aPCCs).
The therapeutically effective substances in aPCCs have been speculated to be various combinations of the following factors: Thrombin, Factor VIIa, Factor IXa, Factor Xa, Factor XIa, Factor XIIa, Prothrombin/Factor Xa complex. However, the precise in vivo mechanism of action for aPCCs is still controversial.